Scleroderma is a devastating autoimmune disease with a chronic course, involving the overproduction of collagen leading to fibrosis of the skin and connective tissues. The disease has a range of symptoms including pain, stiffness and swelling of the joints, shortness of breath and gastrointestinal complications. More than 50% of patients with the aggressive form of scleroderma die or develop organ failure within five years and mortality rates have remained unchanged for four decades. The majority (>75%) of scleroderma patients are women, with initial diagnosis most commonly between the ages of 30 and 50. There are no approved treatments that target the underlying disease process, so current therapies focus on improving symptoms. These include anti-inflammatory drugs (corticosteroids and nonsteroidal anti-inflammatory drugs) and treatments for patient-specific symptoms. There is a major unmet need for more effective and disease- modifying therapies for scleroderma. The pathogenesis of the disease remains poorly understood. Transforming growth factor beta (TGF-) plays a fundamental role, inducing a complete profibrotic gene program, and stimulating generation of reactive oxygen species (ROS). This results in activated myofibroblast accumulation in injured microenvironments leading to fibrosis. The involvement of inflammation and ROS in scleroderma pathogenesis suggests a potential therapeutic role for compounds that activate Nuclear factor-E2 p45-related factor 2 (Nrf2). Nrf2 is a transcription factor which, upon activation in response to inflammatory or oxidative stress, activates a robust anti-inflammatory and cytoprotective transcription program. VEDA-1209 is a specific, potent and orally available Nrf2 activator. The goal of the current Phase I STTR project is to conduct key proof of concept studies to determine VEDA-1209's potential as a novel treatment for scleroderma. The compound's anti-fibrotic activity will be examined in skin biopsies from scleroderma patients as well as in two animal models of the disease. These include an inflammatory model of skin and lung fibrosis induced by subcutaneous bleomycin, as well as a model of skin fibrosis induced by overexpression of the type 1 TGF- receptor. These studies will help to establish the potential for Nrf2 activation as a novel approach for the treatment of scleroderma. If the results of this Phase I project are supportive, we will carry out additional efficacy and mechanism of action studies with VEDA-1209 during the Phase II project period, as well as completing IND- enabling studies to support the subsequent initiation of clinical trials in scleroderma patients.